Methods of treatment, diagnosis and monitoring for methamphetamine toxicity which target ceramide metabolic pathways and cellular senescence

Abstract

Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis, but the molecular mechanism underlying these findings remains unknown. We report now that methamphetamine accelerates cellular senescence in vitro and activates transcription of genes involved in cell-cycle control and inflammation in vivo by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, generated through methamphetamine metabolism via cytochrome P 450 -2D6, which recruit nuclear factor (NF)-KB to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of ceramide formation prevent methamphetamine-induced senescence and attenuate systemic inflammation and health deterioration in rats self-administering the drug. The results support therapeutic approaches to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of treatments.

1 . A method of treating an amphetamine-type drug-induced toxicity, said method comprising administering to the subject in need thereof an effective amount of a modulator of ceramide metabolism or apoptosis which counters an effect of the amphetamine-type drug on ceramide levels or ceramide metabolism or apoptosis. 
     
     
         2 . The method of  claim 1 , wherein the treating reduces, prevents or delays the development of an amphetamine-type drug toxicity selected from induced senescence or organ failure in the subject. 
     
     
         3 . The method of  claim 1 , wherein the toxicity is mediated by an amphetamine-type drug-induced increased ceramide signaling in apoptosis. 
     
     
         4 . The method of  claim 3 , wherein the amphetamine-type drug is administered to the subject before or after the modulator. 
     
     
         5 . (canceled) 
     
     
         6 . The method according to  claim 4 , wherein the modulator is administered from about 15 minutes to about 24 hours before administering the amphetamine-type drug. 
     
     
         7 . (canceled) 
     
     
         8 . The method according to  claim 3 , wherein the modulator is administered at substantially the same time the amphetamine-type drug. 
     
     
         9 . The method according to  claim 4 , wherein the modulator is administered from about 15 minutes to about 24 hours after administering the amphetamine-type drug. 
     
     
         10 . The method of  claim 1  wherein the modulator is a ceramide synthesis inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the modulator which inhibits ceramide biosynthesis is an antisense nucleic acid, a ribozyme, a triplex-forming oligonucleotide, a siRNA, a probe, a primer, an antibody or a combination thereof. 
     
     
         12 . The method of  claim 11 , wherein the modulator targets at least one ceramide-biosynthetic enzyme selected from the group consisting of a sphingomyelinase, serine palmitoyltransferase, 3-ketosphinganine reductase, ceramide synthase, dihydroceramide desaturase, and combinations thereof. 
     
     
         13 . The method of  claim 12 , wherein the modulator binds to the targeted enzyme to inhibit the enzyme or binds to a nucleic acid encoding the enzyme to reduce the expression of the protein. 
     
     
         14 . The method according to  claim 12 , wherein the modulator comprises a compound selected from the group consisting of FB1, D609, myriocin, cycloserine, thalidomide, lenalidomide and combinations thereof. 
     
     
         15 . The method according to  claim 1 , wherein the modulator is adalimumab, golimumab, infliximab, natalizumab, etanercept, Certolizumab pegol, and Pegsunercept. 
     
     
         16 . The method of  claim 1 , wherein the toxicity is atherosclerosis, cardiomyopathy, cardiac infarction, cardiac insufficiency, or a decline in kidney function. 
     
     
         17 . The method of  claim 1  wherein the subject is human. 
     
     
         18 . The method of  claim 1  wherein the amphetamine-type drug is selected from the group consisting of amphetamine, dextroamphetamine, ephedrine, pseudoephedrine, methamphetamine, methylphenidate and the pharmaceutically acceptable salts thereof. 
     
     
         19 . The method of  claim 1 , wherein the modulator is cycloserin. 
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of an amphetamine-type drug; and a therapeutically effective amount of an agent that inhibits ceramide biosynthesis or apoptosis; and a pharmaceutically acceptable carrier. 
     
     
         21 . A pharmaceutical composition according to  claim 20 , wherein the agent that inhibits ceramide biosynthesis targets at least one ceramide-biosynthetic enzymes selected from the group consisting of a sphingomyelinase, serine palmitoyltransferase, 3-ketosphinganine reductase, ceramide synthase, dihydroceramide desaturase, and combinations thereof. 
     
     
         22 . A pharmaceutical composition according to  claim 20 , wherein the agent that inhibits ceramide biosynthesis comprises a compound selected from the group consisting of Fumonisin B1 (FB1), tyclodecan-9-xanthogenate (D609), myriocin and combinations thereof.